美国西奈山医学院（Mount Sinai School of Medicine）研究人员的一项研究表明，与II 型糖尿病发生相关的一种蛋白——增殖物激活受体共激活因子-1α（PGC-1α）同时参与阿尔茨海默症痴呆发作的减缓。这项研究发表在4月6日Archives of Neurology 杂志上。
论文作者之一，神经生物学教授Pasinetti 表示，大约60%的阿尔茨海默症痴呆案例同时伴有其他与II 型糖尿病密切相关的医学症状，其中包括高血糖和对胰岛素的非敏感性等。此前，II 型糖尿病与阿尔茨海默症的关系一直比较模糊：并非所有II 型糖尿病患者同时患有阿尔茨海默症状，也并非所有阿尔茨海默症患者同时遭受糖尿病的侵扰。然而，近年来流行病学证据显示，与健康老年群体相比，同一年龄组的II 型糖尿病患者群体患有阿尔茨海默症的风险增加两倍，其中的原因未知。而近期发表的这项研究则提供了一种可能的机制，有助于解释II 型糖尿病与阿尔茨海默症发生和发展之间的关系。
新研究发现，作为II 型糖尿病治疗靶点，PGC-1α在阿尔茨海默症痴呆患者中含量同样降低。更为重要的是，阿尔茨海默症痴呆患者中PGC-1α含量降低与脑部β淀粉样蛋白含量正相关。这个证据首次表明，在阿尔茨海默症与II 型糖尿病相关的一种基因表达水平之间，存在强相互关系。
利用瞬时转基因阿尔茨海默症小鼠模型，研究进一步表明，小鼠脑部PGC-1α含量的升高削弱高血糖调控的β淀粉样蛋白的合成，从而减缓阿尔茨海默症的发作。研究人员表示，如果药理学研究证明PGC-1α有效，该发现将为阿尔茨海默症的预防性策略和合成新治疗药物提供新切入点。
原始出处：
Arch Neurol. 2009;66(3):352-361.
PGC-1α Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia
Weiping Qin, MD, PhD; Vahram Haroutunian, PhD; Pavel Katsel, PhD; Christopher P. Cardozo, MD; Lap Ho, PhD; Joseph D. Buxbaum, PhD; Giulio M. Pasinetti, MD, PhD
Objectives To explore mechanisms through which altered peroxisome proliferator–γactivated receptor coactivator 1α (PGC-1α) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1 expression in neurons might be developed as a novel therapeutic strategy in AD.
Design Case-control.
Patients Human postmortem brain (hippocampal formation) samples from AD cases and age-matched non-AD cases.
Results Using genome-wide complementary DNA microarray analysis, we found that PGC-1α messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the AD brain. Following confirmatory real-time polymerase chain reaction assay, we continued to explore the role of PGC-1 in clinical dementia and found that PGC-1α protein content was negatively associated with both AD-type neuritic plaque pathology and β-amyloid (Aβ)X-42 contents. Moreover, we found that the predicted elevation of amyloidogenic Aβ1-42 and Aβ1-40 peptide accumulation in embryonic cortico-αhippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dose-dependent attenuation in PGC-1α expression. Most importantly, we found that the reconstitution of exogenous PGC-1 expression in Tg2576 neurons attenuated the hyperglycemic-mediated β-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" α-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression.
Conclusion Therapeutic preservation of neuronal PGC-1 expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Aβ peptides.
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